Review-Symposium

doi: 10.1111/joim.13720

Cognitive dysfunction in post-COVID-19 condition:

Mechanisms, management, and rehabilitation
Marika Möller1 , Kristian Borg1 , Christer Janson2 , Maria Lerm3 , Johan Normark4 & Katarina Niward5
From the 1 Department of Clinical Sciences, Division of Rehabilitation Medicine, Karolinska Institutet, Danderyd University Hospital,
Stockholm, Sweden; 2 Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden;
3
Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden;
4
Department of Clinical Microbiology, Umeå University, Umeå, Sweden; and 5 Department of Infectious Diseases, and Department of
Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden

Abstract. Möller M, Borg K, Janson C, Lerm M, Nor- damage, and latent virus reactivation not exclud-
mark J, Niward K. Cognitive dysfunction in post- ing the possibility of direct viral invasion of the
COVID-19 condition: Mechanisms, management, central nervous system, illustrating complex viral
and rehabilitation. J Intern Med. 2023;294:563– pathology.
581.
As the individual variation of the cognitive impair-
The long-term effects of COVID-19 on cognitive ments is large, a neuropsychological examination
function have become an area of increasing con- and a person-centered multidimensional approach
cern. This paper provides an overview of charac- are required. According to the World Health Orga-
teristics, risk factors, possible mechanisms, and nization, limited evidence on COVID-19-related
management strategies for cognitive dysfunction in cognitive impairments necessitates implementing
post-COVID-19 condition (PCC). rehabilitation interventions from established prac-
tices of similar conditions. Psychoeducation and
Prolonged cognitive dysfunction is one of the most compensatory skills training are recommended.
common impairments in PCC, affecting between Assistive products and environmental modifica-
17% and 28% of the individuals more than 12 tions adapted to individual needs might be help-
weeks after the infection and persisting in some ful. In specific attention- and working memory dys-
cases for several years. Cognitive dysfunctions functions, cognitive training—carefully monitored
can be manifested as a wide range of symp- for intensity—might be effective for people who
toms including memory impairment, attention do not suffer from post-exertional malaise. Fur-
deficit, executive dysfunction, and reduced pro- ther research is crucial for evidence-based inter-
cessing speed. Risk factors for developing PCC, ventions specific to COVID-19-related cognitive
with or without cognitive impairments, include impairments.
advanced age, preexisting medical conditions, and
the severity of acute illness. The underlying mech- Keywords: cognition, fatigue, long-haul COVID,
anisms remain unclear, but proposed contribu- post-acute COVID-19 syndrome, SARS-CoV-2
tors include neuroinflammation, hypoxia, vascular

Introduction than half a billion cases of COVID-19, the coron-

avirus pandemic has led to a huge influx of people
Lingering symptoms after COVID-19 are not
experiencing persistent symptoms in need of acute
uncommon, but symptoms with significant impact
care and rehabilitation. Furthermore, vaccination
on quality of life and functioning following an
prior to SARS-CoV-2 infection is not a fully reliable
acute SARS-CoV-2 infection affect a minority of all
protector against post-COVID-19 condition (PCC)
COVID-19 cases [1–4]. However, as there are more
[3, 5]. According to the World Health Organization
(WHO), PCC is a condition that occurs in adult
From the Think Tank meeting—Long COVID: Multidisciplinary
individuals with a history of probable or confirmed
strategies. SARS-CoV-2 infection, usually 3 months from the

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
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Management of cognitive symptoms in PCC / M. Möller et al.

onset of COVID-19 with symptoms that last for at [CI]: 17%–28%) [19]. Another meta-analysis on
least 2 months and are not explained by an alterna- symptom reports more than 1 year after diagnosis,
tive diagnosis. Thus, the key when diagnosing PCC reported a pooled prevalence of 19% regarding
is to exclude other relevant differential diagnoses difficulties with memory and concentration [20].
[6]. A similar definition was presented by WHO in Substantial heterogeneity across studies has
February 2023 for PCC in children and adoles- been observed in the aforementioned studies. The
cents, with some differences in the clinical picture cognitive symptoms in PCC often fluctuate and,
compared with adults [7]. Studies on and descrip- in some cases, worsen over time [21]. The term
tions of PCC uncover a wide spectrum of clinical “brain fog” is not a medical condition and lacks a
manifestations involving different organ systems— scientific definition. Rather it is an umbrella term
including but not limited to severe fatigue, short- used to describe the difficulty in thinking clearly,
ness of breath, cognitive dysfunction, palpitations, which is commonly seen in various disorders that
chest pain, prolonged fever, anosmia or ageusia, affect processing speed and attention functions.
vertigo and tinnitus, headache, peripheral neu- Patients experiencing brain fog often describe
ropathy, skin rash, and joint pain or swelling [4, 8, themselves as disorganized or confused, having
9]. Symptoms included in PCC may appear in clus- trouble focusing, or struggling finding words [22].
ters or be monosymptomatic. Furthermore, they Comorbid conditions are common, including sleep
may fluctuate or relapse over time and often have disturbances, anxiety, and depression [16, 17, 19].
an impact on everyday functioning [6]. For most
people suffering from PCC, the symptoms will grad- In a comprehensive analysis of retrospective
ually resolve over time, but for some, they will propensity-score matched cohort studies span-
linger on for many months and even years after the ning a 2-year period involving 1,284,437 patients
initial infection [1, 10–14]. diagnosed with SARS-CoV-2, Taquet et al. discov-
ered that the risks of mood and anxiety disorders
Collaborative research to deepen the understand- diminished after 1–2 months and did not exhibit
ing of risk factors, mechanisms, and prognosis of a notable increase after 2 years. However, the
PCC is urgently needed as well as to promote the risks of cognitive deficit, dementia, psychotic
development of preventive and therapeutic strate- disorders, and seizures remained elevated even 2
gies. Today, progress has been made to reduce years after the infection. Additionally, Taquet et al.
the risk of developing PCC, but specific medical observed no differences in risks of neurological and
treatment is still lagging. This review will focus on psychiatric outcomes between infections caused
cognitive aspects of PCC in patients with an ini- by the Omicron (B.1.1.529) or Delta (B.1.617.2)
tial non-critical SARS-CoV-2-infection, and cover variants at the 3-month follow up. The study
characteristics, risk factors, possible mechanisms included both hospitalized and non-hospitalized
and provide an approach to management and patients, although the results were not stratified
rehabilitation. Physiological aspects of PCC are by severity of illness [11]. In a cohort consisting
covered in a recent article by Fedorowicz et al. [15]. of 65 COVID-19 patients treated in the intensive
For those experiencing long-term post-COVID-19 care unit (ICU) at Danderyd University Hospital
symptoms, the possible explanatory mechanisms in Stockholm, we discovered no major disparities
may not be the same as in the critically ill patients in cognitive outcome between patients treated
treated in mechanical ventilation, and this review during the first pandemic wave compared to those
will not discuss post-intensive care syndrome in treated in subsequent waves, despite the longer
COVID-19 patients. duration of ICU stay during the first wave (26 vs.
9 days) (Möller 2023, personal communication). In
a prospective multicenter cohort study in Sweden
Characteristics of cognitive symptoms in PCC [14], we found a high prevalence of persistent cog-
The most frequently reported symptoms in PCC nitive symptoms 6 months after infection both in
are fatigue and cognitive symptoms of “brain non-hospitalized (168/283, 59%) and hospitalized
fog,” memory problems, decreased concentra- patients (119/151, 79%). In a long-term follow-up
tion and impaired attention [16–18]. In a large population-based study of 165 patients diagnosed
meta-analysis on symptom reports more than 12 with PCC at 4 months post-discharge from any
weeks following COVID-19 infection, the pooled hospital in Region Östergötland in Sweden [10], we
proportion of individuals experiencing cognitive found that the majority of patients (139/165, 84%)
impairment was 22% (95% Confidence Interval reported persisting problems affecting everyday

564 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

life at the 2-year follow-up, and approximately Cognitive symptoms

half of the patients who were on sick leave related
Attention functions enable the ability to process
to PCC at 4 months after infection were still on
information from our surroundings and are con-
sick leave. The most common persisting symp-
sidered to be hierarchical in nature [29]. Focused
toms were cognitive, sensorimotor, and fatigue
attention and sustained attention are regarded as
symptoms, and we observed no difference between
fundamental attention functions. Higher levels of
individuals treated in the ICU and non-ICU-
attention rely on executive functions and encom-
treated individuals. In patients with initial mild
pass alternating, selective, and divided attention.
infection, the correspondence between self-rated
Despite its name, working memory is also consid-
cognitive symptoms and outcome of neuropsycho-
ered a function of attention [29, 30] and plays a
logical assessment is less clear. Some follow-up
significant role in encoding memory and retriev-
studies report no significant differences between
ing information stored in long-term memory [31].
individuals 4 months after COVID-19 diagnosis
Given that attention functions serve as fundamen-
and healthy controls [23], whereas studies on
tal cognitive processes and subsystems for other
symptomatic patients do find differences between
cognitive functions, they are crucial for manag-
those with verified COVID-19 infection and those
ing our everyday life. Impaired attention functions,
without in terms of lower performance compared
even in the cases of mild impairments, directly
with demographically matched norms on tests of
affect performance in both everyday tasks and
attention and working memory [16]. Larger studies
work life [32].
with appropriate control groups are lacking.
Attention functions are frequently associated with
It is not clear whether lingering symptoms included
processing speed. From a neuroanatomical per-
in PCC differ from what can occur after other res-
spective, the thalamus plays a crucial role as a
piratory viral infections. In a large retrospective
hub in networks that support processes related
cohort study of nearly 250,000 survivors of COVID-
to attention, information processing, memory, and
19, neurological and psychiatric outcomes after 6
executive functions [33]. However, in the stud-
months were compared with those of patients with
ies carried out so far on COVID-19, it has not
influenza [11]. The risk of intracranial hemorrhage
been determined which of the attention functions
and ischemic stroke was higher in the COVID-
is most affected in PCC, nor to what extent other
19 group, and there was a preliminary associa-
cognitive dysfunctions are independent or linked
tion with dementia, anxiety, and mood disorders
to decreased attention functions. Impairments in
as well as insomnia. The risk increased with the
attention, working memory, and executive func-
severity of the COVID-19 infection but was also
tions often have secondary effects on tests assess-
found in patients who did not require hospitaliza-
ing memory encoding and retrieval. Consequently,
tion. Furthermore, the reported long-term cogni-
episodic memory can indirectly be affected by the
tive symptoms and fatigue are not specific for PCC.
type of neurological damage caused by viral dis-
Rather, they resemble what often can be seen in
eases, primarily through reductions in attention
several other conditions such as mild traumatic
and processing speed required for encoding [34]. In
brain injury [24], stroke [25], or multiple sclero-
the context of PCC, it is still not fully established
sis [26]—that is, decreased attention and memory
whether the results observed in memory tests stem
functions, reduced processing speed, and fatigue.
from primary difficulties in memory storage or if
The phenotypes of these disabilities are possibly
they are secondary effects resulting from impaired
related to the functional anatomy of the brain,
attention and/or working memory.
although the underlying mechanisms behind dif-
ferent conditions may be different. There is also
an overlap with myalgic encephalomyelitis/chronic Fatigue
fatigue syndrome (ME/CFS) as further presented Fatigue is a prominent symptom in both acute
below. Common to all these conditions is that sub- COVID-19 and PCC. Prevalence rates for post-
jective cognitive complaints may not be associated COVID fatigue range from 32% to 46% in differ-
with objective cognitive test results. Moreover, psy- ent studies [17, 19, 35] and in meta-analysis of 1-
chological distress can interfere with self-reported year follow-ups between 18% and 39% [20]. How-
symptoms [16, 27, 28]. The most common cognitive ever, fatigue is a multifactorial and vaguely defined
symptoms after COVID-19 are further described symptom present in various conditions including
later. neurological disorders [36], chronic pain [37], and

© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 565
Journal of Internal Medicine, 2023, 294; 563–581
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Management of cognitive symptoms in PCC / M. Möller et al.

depression [38]. Post-infectious fatigue has also one of our studies in Sweden [14], hospitaliza-
been reported after other viral epidemics [39]. In tion was the main risk factor for developing PCC
most studies, fatigue is subjectively reported using and reduced health-related quality of life 6 months
self-assessment scales designed to capture a low after infection. Markers of systemic inflammation
energy level not in proportion to the individual’s are associated with persisting fatigue and cogni-
activity level and that is not alleviated by nor- tive symptoms with marked functional impairment
mal rest or sleep [40, 41]. Currently, there is no [19], and reports indicate a large proportion (40%–
validated fatigue scale specifically for post-COVID 80%) of hospitalized patients experiencing post-
fatigue. As COVID-19 is a novel condition, it is COVID sequalae with neuropsychiatric symptoms
not evident whether the fatigue experienced in PCC [19, 48, 49]. In line with this, vaccination against
is equivalent to and shares the same underly- SARS-CoV-2—which for most people confers less
ing mechanisms as fatigue in neurological condi- risk of severe COVID-19—seems to decrease the
tions. In neurological conditions, decreased atten- risk of developing PCC after infection [3, 5].
tion [42], slowed processing speed [43], and fati-
gability [44] have been linked to the experience Psychiatric comorbidity
of fatigue but have also shown significant correla-
Mental conditions—that is, disorders affecting the
tions with depression [45] and sleep disorders [46].
central nervous system such as major depres-
How eg. sleep disturbances, depression or pain are
sive disorder and autism spectrum—have been
related to self-rated fatigue in PCC are not clear.
reported to be an increased risk for infection of
Nonetheless, in a study by Calabria et al. on 136
COVID-19 [11, 50, 51]. However, in the study by
COVID-19 patients with cognitive complaints—
Merzon et al. [52], there was no increase of depres-
assessed with both neuropsychological tests and
sion in the COVID-19 cohort. People with atten-
Modified Fatigue Impact Scale—clinically signifi-
tion deficit hyperactivity disorder (ADHD) have
cant fatigue was reported in 82.3% of the par-
been reported to have a higher risk for contracting
ticipants on average 8 months after SARS-CoV-2
COVID-19 infection, especially the patients with-
infection (both hospitalized and non-hospitalized
out pharmacological treatment [52]. Merzon et al.
patients). Different types of fatigue were related to
[52] speculated that pharmacotherapy for ADHD
distinct psychological and cognitive factors [47].
moderated the risk due to an increase of aware-
ness of preventive actions, and Cortese et al. [53]
Risk factors for PCC encouraged ADHD treatment in order to reduce the
spread of COVID-19. The study by Heslin et al. [50]
A recent meta-analysis by Tsampasian et al. [5]
reported an increased risk for ADHD patients to
stated that female sex (odds ratio [OR], 1.56; 95%
contract COVID-19 infection but also an increased
CI, 1.41–1.73), age (OR, 1.21; 95% CI, 1.11–1.33),
risk to contract influenza, which may indicate that
high BMI (OR, 1.15; 95% CI, 1.08–1.23), and smok-
this finding is not specific for COVID-19. How-
ing (OR, 1.10; 95% CI, 1.07–1.13) were associ-
ever, ADHD patients had a reduced risk of severe
ated with an increased risk of developing symp-
outcomes such as hospitalization and mechani-
toms of PCC also in non-hospitalized cases. The
cal ventilation [50], which may be due to the age
presence of comorbidities and previous hospital-
of the patients. This was contradicted by data
ization including ICU admission were found to be
showing that the association of ADHD with less-
associated with even higher risk of PCC (OR, 2.48;
severe COVID-19 outcomes was only significant
95% CI, 1.97–3.13 and OR, 2.37; 95% CI, 2.18–
for the older age group [50]. Different confounders
2.56, respectively). However, this meta-analysis
were discussed considering biological effects as
refers to symptoms in general and not separating
an explanation via pharmacotherapy and elevated
cognitive symptoms. Clinically, we have noted a
inflammatory processes that may induce alter-
higher percentage of women (approx. 70%) seek-
ations in the immune and antiviral systems [50].
ing care for cognitive post-COVID symptoms after
Thus, it is still not obvious whether the increased
an initial non-critical acute SARS-CoV-2 infec-
rate of mental disorders in COVID-19 is due to a
tion at the cognitive post-COVID clinic at Dan-
biological or to a social factor.
deryd University Hospital (Möller, personal com-
munication). The incidence of PCC is estimated
Myalgic encephalomyelities and similarities with PCC
to be higher among hospitalized COVID-19 cases
compared with non-hospitalized [8, 20]. Thus, the PCC shares symptoms with ME/CFS which is
initial disease severity is an important factor. In characterized by mental fatigue and fatigability as

566 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

well as cognitive difficulties lasting more than 6 but in this context, it is important to bear in mind
months [54] and post-exertional symptom exacer- that some brain functions are more readily affected
bation (PESE) also referred to as post-exertional than others [68]. Acquired knowledge is consid-
malaise (PEM), defined as exacerbation of symp- ered resistant to brain injuries, whereas the abil-
toms after minimal cognitive, physical, emotional, ity to solve novel problems, attention functions,
or social activity, or activity that was previously tol- and episodic memory are more susceptible to both
erated [55]. Symptoms typically intensify 12–72 h external disruptions such as brain injuries [69] as
following activity and can last for days or even well as to inner states [70]. Below we discuss dif-
weeks, sometimes leading to a relapse [56]. PESE ferent possible mechanisms behind PCC including
can contribute to the episodic nature of disability applicable theories for long-term cognitive symp-
in PCC, often presenting as unpredictable fluctua- toms in PCC (see Fig. 1).
tions in symptoms and function [56].
Direct injuries during acute SARS-CoV-2 infection
ME/CFS is characterized by WHO as a neurological
disorder, but the etiology of ME/CFS is unknown. As an obligate intracellular parasite without a
More than half of the patients report onset of symp- metabolism of its own, the virus uses the host
toms after a virus infection [57]. Jason et al. (2021) nucleic acid machinery to reprogram the host
compared symptoms of the patients with PCC to for reproduction and induces cell apoptosis,
those of patients with ME/CFS, and the PCC symp- autophagy, and programmed necrotic cell death
toms were less intense with the exception of ortho- [71]. The level of cellular damage is related to
static problems. The symptoms of the patients with the level of viremia which in turn is beholden
PCC decreased with time in contrast to the symp- to virulence—that is, the infectiveness, the effec-
toms of the patients with ME/CFS. However, this tiveness in control over cellular metabolism, and
was not the case with problems such as trou- ability to avoid innate and acquired immunity
ble forming words, difficulties focusing and absent [72, 73]. The ability to exploit the Angiotensin
mindedness which remained unchanged in the Converting Enzyme-2 (ACE2) protein as a recep-
patients with PCC [58]. In our PCC outpatient clinic tor for entry into the cell to commandeer cellu-
at Danderyd University Hospital, we find patients lar machinery is central to inducing cell injury
with PCC with a considerable overlap of ME/CFS [74]. ACE2 is an essential protein in cell mem-
(Borg and Möller 2023, personal communication), branes that catalyzes angiotensin II to I and is
which is corroborated by findings of the studies of involved in the renin–angiotensin–aldosterone sys-
Kedor et al. [59] and Twomey et al. [60] reporting tem essential for blood pressure control and home-
that around half of the patients with PCC were esti- ostasis [75]. Viral-induced cell death results in
mated to meet the criteria of ME/CFS. A cytokine loss of ACE2 action in the entire body [76, 77].
increase has been reported in ME/CFS [61] and Direct damage at the organ level includes multi-
also found in PCC [62]. In the study by Haffke et al. ple sites of injury, including brain stem inflam-
[63], endothelial dysfunction of the same kind as mation and hypothalamic-pituitary axis dysfunc-
found in ME/CFS was reported in PCC. Further- tion [78]. It is known that the SARS-CoV-2 virus
more, Peluso et al. [64, 65] reported reactivation can infect neural cells [79]. Several mechanisms
of viruses including Epstein-Barr virus (EBV) also have been proposed despite scant data supporting
described in ME/CFS [66]. Thus, one may specu- neuroinvasive routes [80], especially as ACE2 and
late that PCC and ME/CFS have a common etiology the transmembrane serine protease 2 (TMPRSS2)
or that they represent post-viral conditions with a receptor—an essential co-receptor for SARS-CoV-2
common pathogenesis. cell entry—are not expressed by the cells in CNS
[81] but rather by brain endothelial cells. Hypoxia
has been shown to alter the dynamics in ACE2 and
Explanatory models for long-term cognitive symptoms after TMPRSS2 expression in this cell type [82]. Viral
COVID-19 access to these cells may affect endothelial func-
tion and in turn cause neural tissue injury [83].
Today, there is still insufficient knowledge of what
causes cognitive dysfunctions in patients with PCC
Hypoxia: central and peripheral
and even less knowledge of the most effective
rehabilitation efforts. Different pathophysiological Cardiorespiratory fitness as well as peak oxy-
events explaining remaining symptoms after infec- gen uptake and left ventricular ejection fraction
tion of SARS CoV-2 virus have been discussed [67], has been shown to be associated with cognitive

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Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

Fig. 1 Possible pathophysiological mechanism in cognitive impairment of post-COVID-19 condition (PCC).

function [84] and cognitive impairment in patients cular dysfunction. SARS-CoV-2 triggers endothe-
with chronic heart failure [85]. Hypoxia is one lial exocytosis, which results in microvascular
possible mechanism of cognitive symptoms after thrombosis and inflammation [93] leading to
COVID-19. Silent hypoxia and poor oxygenation endothelial dysfunction and vascular leak. Post-
despite relatively minor parenchymal involvement mortem analysis of pulmonary capillaries in
is common especially in the early stages of COVID- COVID-19 cases demonstrated capillary plugging
19 [86, 87]. The patients often have a high respi- from fibrous microthrombi, suggesting that sys-
ratory drive and dyspnea, but the respiratory rate temic thrombosis is a primary mechanism of pul-
is often normal. Lung computed tomography imag- monary COVID-19 infection [94]. The endothelial
ing, lung gas volume, and respiratory mechanics dysfunction seen in COVID-19 can also be related
are also nearly normal. Pulmonary embolism is to hemoglobin released from damaged erythro-
common in COVID-19, with a higher prevalence in cytes that scavenges endothelial NO and thereby
critically ill patients [88]. The underlying mecha- contributes to oxidative stress and hypoxia [95].
nism behind the hypoxia is primarily altered lung A case study reported improvement in a patient
perfusion possibly caused by a combination of pul- with PCC who was seropositive for a number
monary embolism and ventilation-perfusion mis- of autoantibodies targeting G-protein-coupled
matching [89, 90]. Alveolar wall damage could also receptors (GPCRs), and who was treated with an
contribute to the hypoxia. This mechanism is sup- aptamer directed to inactivate GPCR autoantibod-
ported by the fact that many patients with COVID- ies. The authors noted measurable improvement
19 have a decreased diffusing capacity (DLco), and of microcirculation in the eyes and of the general
this impairment often remains at follow-ups [91]. PCC symptoms and proposed that the impaired
In one study of hospital survivors with COVID-19, microcirculation observed in PCC is linked to
no improvement in 6 MWT and DLco was found GPCR autoantibodies [96].
between 6 and 12 months [92]. In a 2-year study,
steady improvement was seen in symptoms, health A small study has reported amyloid-like micro-
status, and psychological status after hospitaliza- clots, up to a diameter of 200 µm, in 11 patients
tion due to COVID-19, but still sequelae were rela- with PCC compared with healthy controls [97]. The
tively common as was DLco impairment [13]. clots were resistant to fibrinolysis, and because of
their size, they may cause occlusion of capillaries
and ischemic damage to the neurons [98]. The
Microvascular inflammation and microthrombosis small cohort sizes of the study, the heterogeneity,
The cognitive impairment in COVID-19 could and the difficulty in the characterization of the
also be related to microvascular inflammation. condition have to be considered when evaluating
Severe COVID-19 is characterized by microvas- the importance of microthrombosis to PCC. We

568 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

have not found any large prospective observational studies have failed to identify SARS-CoV-2 in
clinical studies that could confirm this finding. A the autopsied brain or in CSF of live patients
study from the same authors (n = 25 cases of PCC) hospitalized due to COVID-19 [109–114]. In
showed biomarker evidence of thrombotic endothe- patients suffering from PCC, data are even more
liitis in the patients in which these markers are scarce and limited to case reports presenting
suggested to be indicators of PCC [99]. However, residual viral antigens in CSF or tissues [115,
the dysregulation of procoagulant and fibrinolytic 116]. In sum, there is so far insufficient evidence
pathways in patients with PCC has been observed to conclude that direct or persisting CNS infec-
elsewhere as well [100]. There is also an aspect tion by SARS-CoV-2 itself explains the long-term
of autoimmunity that may play a role in the for- neurological and/or neuropsychiatric symptoms
mation of microclots in PCC. In a study by Zuo of COVID-19.
et al., 52% of patients treated in hospital due to
COVID-19 exhibited prothrombotic autoantibodies Reactivation of latent herpesviruses
targeting phospholipids and phospholipid-binding
In PCC, signs of reactivated latent virus infec-
proteins [101]. This has to our knowledge not been
tions, such as EBV, human herpesvirus (HHV)-
confirmed in matched case-control studies of PCC.
6, and HHV-7, have been observed [64, 66, 117],
and in vitro studies show mitochondrial fragmen-
Ongoing systemic inflammation, neuroinflammation,
tation and impaired energy metabolism as a result
and autoimmune aspect
of the response to reactivated herpesvirus [118].
High levels of autoantibodies, including against In a cohort of 280 adults with prior SARS-CoV-
ACE2, were found in patients with PCC and 2 infection, lingering fatigue and cognitive dys-
were inversely correlated with antibodies against function were independently associated with sero-
COVID-19 antibodies [102]. Another possible logical pattern, suggesting recent EBV reactiva-
mechanism that has been proposed is that inflam- tion [64]. In another study, suggesting COVID-19
mation in the airways and lung causes neu- inflammation-induced EBV reactivation as a pos-
roinflammation [103]. In a paper by Fernandez- sible driver of PCC, two-thirds of the patients with
Castaneda et al., mice were infected in a way that persisting symptoms post-COVID versus 10% in
limited the infection to the respiratory system the control group were positive for EBV reactiva-
[104]. This resulted in increased levels of cytokines tion [119]. Furthermore, Verma et al. suggested a
in the cerebrospinal fluid (CSF), whereof one synergistic relationship between SARS-CoV-2 and
was C–C motif chemokine ligand 11 (CCL11)—a EBV by demonstrating that lytic replication of EBV
chemokine associated with cognitive impairment induces increased ACE2 expression in cultures
[105]. The authors also found impaired hippocam- of epithelial cells, thereby enhancing the entry of
pal neurogenesis, decreased oligodendrocytes, and SARS-CoV-2 in the cells [120].
myelin loss in the infected mice compared to con-
trol mice. Interestingly, similar findings were found Epigenetic response
in human postmortem SARS-CoV-2 infection. Fur-
There is growing evidence to suggest that viral and
thermore, elevated CCL11 levels were found
bacterial infections can lead to epigenetic changes
in humans with persisting cognitive symptoms
in the host, which can affect the host’s immune
post-COVID [104]. Taken together, these findings
response and the severity of the infection [121–
indicate that airway inflammation causes inflam-
123]. Epigenetic changes refer to alterations in the
mation of the nervous system through release of
way genes are expressed rather than changes in
systemic chemokines such as CCL11 [103].
the underlying DNA sequence itself [124]. COVID-
19 has been shown to induce epigenetic changes
Low-level persistence of SARS-CoV-2 viral antigens in
such as a modified DNA methylome also in healthy
CNS
convalescents [125, 126]. More recently, evidence
The presence of viral antigens in the CNS may trig- shows that PCC is associated with certain DNA
ger an immune response with cytokine activation, methylation changes [127, 128]. In one of these
leading to inflammation damaging the nervous studies [127], strong epigenetic modifications were
system. Low levels of viral RNA have been detected reported in genes involved in the electron trans-
by PCR in some autopsy studies [106–108], but port chain in mitochondria. Of note, DNA methy-
evidence of causality between virus and COVID- lation changes to genes involved in mitochon-
associated neuropathology is controversial. Many drial function have also been reported in ME/CFS

© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 569
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

[129, 130] with similarities to PCC as described The remaining 384 persons were included as con-
above. In addition, our unpublished data point trols. The study identified not only changes in
toward enrichment of EBV infection-related path- olfactory pathways and orbitofrontal cortex but
ways in the altered epigenomes of patients with also a greater reduction in global brain size and on
PCC, further corroborating the notion that EBV average a greater cognitive decline between the two
reactivation may be mechanistically involved in time points among SARS-CoV-2 cases compared
PCC. with the controls. As the study used preinfection
imaging data, preexisting risk factors being mis-
interpreted as disease effects were reduced. The
Correlates to imaging findings effects were still observed after excluding patients
The abovementioned explanatory models may have who had been hospitalized. The authors concluded
the potential to contribute to residual cognitive that the limbic brain imaging results may be the
symptoms and fatigue. These effects may not in vivo hallmarks of a degenerative spread of the
necessarily manifest as detectable organic brain disease through olfactory pathways, of neuroin-
injuries. However, various outcomes have been flammatory events, or of the loss of sensory input
reported in magnetic resonance imaging (MRI) due to anosmia [134]. These results are interest-
and positron emission tomography studies of ing because in functional MRI studies, fatigue has
brain volume and metabolism in patients after been related to disturbed attention functions and
COVID-19 infection. In a study by Martini et al. altered connectivity in fronto-striatal networks in
[131], severe hypometabolism was seen during the other patient groups [135]. Furthermore, in normal
acute infection but after 7–9 months postinfec- aging, decreased mental processing speed has been
tion, no hypometabolism was detected. Rather, correlated to decreased connectivity in cortico-
brain hypermetabolism was detected in the brain- striatal networks in the brain [136]. As for COVID-
stem, cerebellum, hippocampus, and amygdala 19 fatigue, regional hypo- and hypermetabolism
and was correlated to the inflammatory status were found in several areas in the frontal lobe,
[131]. Martini et al. (2022) suggested a syner- and smaller volumes of the frontal lobe areas were
gistic effect of virus-mediated inflammation and correlated with fatigue [137]. However, radiologi-
transient hypoxia leading to dysfunction of the cal findings in COVID-19 should still be interpreted
fronto-insular cortex. On the other hand, Dress- with caution as differences in outcome may be due
ing et al. [132] reported no significant changes of to such factors as severity of initial infection, time
regional cerebral glucose metabolism, and func- since illness, methodological differences, or demo-
tional imaging showed no distinct pathological graphics.
changes in a long-term phase after COVID-19. Fur-
thermore, cognitive testing showed minor abnor-
Other post-viral cognitive syndromes
malities on an individual level. In a study of
56 patients with mild-to-moderate COVID-19 and Lingering cognitive symptoms have been reported
37 controls, Bispo et al. [133] found no differ- in several viral infections. A review by Hassan
ences in neuropsychological performance or gray Ahmed and collaborators identified 28 scientific
matter volume between the patients with mild- articles related to long-term clinical outcomes in
to-moderate COVID-19 and the controls, but the survivors of previous coronavirus outbreaks such
patients with COVID-19 had lower fiber density as SARS and Middle East Respiratory Syndrome
in the association, projection, and commissural (MERS). A meta-analysis revealed that beyond
tracts. However, fatigue scores, reaction time, and 6 months after hospital discharge, individuals
visual memory tests correlated with microstruc- experienced lung function impairment, reduced
tural changes in the COVID-19 group, suggest- exercise capacity, and psychological issues such as
ing possible brain substrate underlying the symp- anxiety, depression, and posttraumatic stress syn-
toms during recovery (approximately 3 months) drome [138]. Health related quality of life remained
from COVID-19 [133]. low up to 6 months post-discharge, and cognitive
dysfunctions related to attention and memory
In a large study with data from the UK Biobank, were reported in up to 15% of individuals infected
785 participants had been imaged twice using MRI, by SARS or MERS. Similarities between influenza
and 401 of the participants tested SARS-CoV-2- and SARS-CoV-2 infections highlight the potential
positive between the two scans. The average time of respiratory infections to trigger neuroinflam-
between diagnosis and second scan was 141 days. mation, impacting neural-cell function. Moreover,

570 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

there are overlapping symptoms between PCC bilitation, and the rehabilitation of psychiatric
and the encephalitis lethargica epidemic (von populations has demonstrated potential benefits
Economo’s encephalitis) of the 1920s (e.g., fatigue, of computerized cognitive training [148]. As pre-
cognitive impairment, and headache), which was sented in WHO recommendations [149], specific
hypothesized to be causally related to the 1918 evidence for training programs targeting COVID-
Spanish influenza pandemic [139]. Other neu- 19-related cognitive impairments predominantly
rotropic viruses that give rise to viral meningitis, relies on experiences and knowledge gained from
including Varicella zoster virus, enteroviruses, and cognitive dysfunctions caused by other factors.
Herpes simplex virus (HSV), induce neurological Given that fatigue and mental health symptoms
sequalae in the aftermath of infection. A large study overlap or tend to present in clusters, these fac-
of viral meningitis in the United Kingdom covering tors as well as demographic factors should be con-
1126 patients showed significantly lower quality of sidered when designing rehabilitation programs.
health [140]. These patients reported higher inci- The WHO recommends an individualized approach
dences of pain, anxiety and depression, with HSV using a combination of education, skills training on
patients scoring the highest. Arboviruses, such self-management strategies, and cognitive train-
as tick-borne encephalitis (TBE), also give rise to ing. Furthermore, training in the use of assistive
neurological sequalae. A study of TBE showed a products and environmental modifications is sug-
low fatality rate, but a considerable number of gested as they apply to daily functioning.
individuals developed postencephalitic syndrome
characterized by mental disorders, balance and Functional cognitive retraining includes systematic
coordination issues, and headaches. The risk of interventions that gradually increase in difficulty
permanent sequelae increased with age [141]. with the aim of either (1) retraining reduced func-
Dengue, another arbovirus, has also been asso- tions directly by targeting the underlying pro-
ciated with a higher risk of developing dementia cesses or (2) implementing specific compensatory
[142]. Parvovirus B-19 has been linked to neu- behaviors that help mitigate the impact of reduced
rological symptoms, with encephalitis being the function indirectly. The type of impairment deter-
most common manifestation, and some patients mines which rehabilitation principle should be
experienced long-term neurological deficits. A sys- used. Regardless of the choice of training method,
tematic review [143] showed that 61% of the total all cognitive rehabilitation is based on the premise
cohort experienced neurological symptoms in the that the individual is motivated to engage in train-
aftermath of the acute Parvovirus B-19 infection. ing. For optimal treatment outcomes and sustained
results, it is important to provide opportunities for
Immunomodulatory treatment studies have shed generalization of strategies to everyday activities by
some light into the pathogenesis of neurological incorporating metacognitive aspects (reflecting on
post-viral symptoms. Poliomyelitis virus that also one’s own cognitive processes) in the training as
affects the nervous system may lead to flaccid well as including strategies for emotional regula-
paralysis due to damage to the anterior horn cells. tion, endurance in training, and motivation [150].
In patients with post-polio syndrome—that is, a However, some impairments—such as poor mem-
late increase of weakness of muscles and fatigue— ory functions and certain executive functions—
Gonzalez et al. [144] reported a CNS inflamma- cannot be functionally trained. In such cases, com-
tion with an increase of different cytokines includ- pensatory training must be offered.
ing increased numbers of CSF cells expressing
mRNA for TNF-alpha, IFN-gamma, IL-4, and IL- Compensatory training involves communicating
10. Immunomodulatory treatment reduced IFN- alternative behaviors or action sequences to cir-
gamma and TNF-alpha levels dramatically [145]. cumvent difficulties and optimizing performance
by using strategies that enhance skills for func-
Management and rehabilitation of cognitive dysfunction tional abilities and minimize situations that may
after COVID-19 lead to repeated failures. This approach relies on
learning to employ a range of external and internal
Cognitive rehabilitation self-management strategies to establish a changed
Studies on cognitive rehabilitation for patients with pattern of behavior. These can vary from simple
persisting symptoms after COVID-19 are scarce everyday tips, such as using post-it notes to com-
[146, 147]. A proof-of-concept study drawing upon pensate for poor memory, to cognitively demanding
principles used in acquired brain injury (ABI) reha- processes [150, 151].

© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 571
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

Fig. 2 Flowchart on proposed assessments and rehabilitation interventions for patients with post-COVID-19 condition (PCC)
with cognitive symptoms and fatigue.

Below, principles are described for the rehabili- underlying cognitive processes that contribute to
tation of certain specific functional impairments the dysfunctions, as well as to determine cognitive
commonly reported by patients with PCC. These resources that can be used to compensate for
are based on existing knowledge about rehabili- impairments that cannot be trained. Based on
tation of acquired brain injuries. As the suffering the result of the neuropsychological assessment
is great among those affected, we need to offer and evidence from other conditions, specific train-
safe interventions while evaluating these care- ing methods (described and further visualized
fully and taking evidence-based medicine into in Figs. 2 and 3) can be offered by therapists
account [152]. As some patients may experience with expertise in cognitive rehabilitation. The
severe fatigue and worsened symptoms with inten- rehabilitation can be guided by one or more ther-
sive cognitive interventions, close monitoring of apists depending on the complexity. However,
intensity levels and careful observation for any it is also important to remember that PCC can
signs of deterioration are important. On the other be very complex, and patients can have one or
hand, compensatory strategies should be possi- more cognitive dysfunctions, ranging from mild to
ble to implement safely. To effectively implement severe. In addition, the patient may suffer from
the rehabilitation methods mentioned below, we other somatic ailments or psychological symptoms
suggest that the patient rehabilitation program is which more or less also affect the cognitive diffi-
person-centered and individualized. It is important culties. These need to be treated in parallel and
to start with a medical examination by a physician to be taken into account when planning further
to rule out underlying medical conditions that rehabilitation. Which health professions should
need to be addressed first and to rule out that be involved in the rehabilitation process may vary
the patient is suffering from extensive PEM/PESE, depending on the type of rehabilitation but also
making demanding rehabilitation efforts inappro- differ both nationally and internationally depend-
priate. Next, a neuropsychological assessment ing on economic and cultural factors. Most often,
should be conducted by a neuropsychologist to psychologists, occupational therapists, and speech
determine the patient’s cognitive dysfunctions and therapists are involved in cognitive rehabilitation.

572 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

Fig. 3 Rehabilitation strategies for fatigue and different cognitive dysfunctions.

A proposal for rehabilitation therapy is visualized information processing speed or impaired ability
in Fig. 3. to manage time, Time Pressure Management has
been recommended as a compensatory strategy
Attention and processing speed. In ABI, specific for patients following an ABI [153].
attention training that includes metacognitive
strategy training has been shown to be effective Memory. If memory problems are attributed to
in retraining function and developing compen- reduced memory span or working memory lead-
satory strategies that promote generalization to ing to, for example, decreased prospective mem-
everyday activities [150, 153]. One well-evaluated ory, functional training targeting these underly-
attention training method is Attention Process ing functions is recommended (see above). How-
Training, which is based on a cognitive model of ever, when memory storage itself is primarily
attention [154]. Computer-based training methods affected, functional training alone lacks support-
targeting working memory have also been shown ing evidence. Nonetheless, there is some evidence
to be effective if conducted with the support of a for strategy training as a compensatory approach
therapist who provides continuous follow-up and to address impaired memory. Memory strategy
feedback during the training. However, when used training encompasses various techniques, some of
in isolation, computer-based training has limited which are tailored to specific difficulties, whereas
evidence of improvements to other functional areas others aim to enhance awareness of the conse-
[153]. Training interventions targeting decreased quences of memory impairment in practical sit-
attention and processing speed have demon- uations. Specific training may focus on remem-
strated potential effect on fatigue in other patient bering names, developing routines, or establish-
groups [155]. However, considering that many PCC ing systems for organizing personal belongings.
patients are easily fatigued, it may be preferable These strategies can also incorporate the use of
to initially prioritize compensatory strategies until aids that provide an overview or electronic mem-
it is determined whether the patient can tolerate ory aids that offer reminder functions. Patients
functional training. For patients with reduced with mild memory impairments may have better

© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 573
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

cognitive reserves, enabling them to employ inter- effect is less certain in ME/CFS and systemic
nal strategies such as association techniques for exertion intolerance disease for which exercise
compensation [153]. increases fatigue [159]. According to WHO liv-
ing guidelines, a cautious return to physical
Executive functions. Executive impairments have exercise training is suggested via a combina-
a range of manifestations including both subtle tion of education and skills-training on energy
behavioral changes such as difficulties in emo- conservation techniques [149]. Physical activity
tional regulation and self-monitoring, as well should be guided by the presence and severity of
as specific impairments such as difficulties in symptoms and can be titrated up and down to
problem-solving skills, activity regulation (ini- avoid exacerbating symptoms. It is important to
tiation and inhibition), decision-making, and exclude PEM before commencing exercise therapy
evaluation. Training of executive functions targets and consider careful monitoring for PEM both
the enhancement of integrative processes that during and after exercise [160, 161]. For patients
regulate goal-oriented and purposeful behavior with symptoms of PESE/PEM, the stabilization of
aiming for the patient to acquire strategies to symptoms needs to be secured before increasing
compensate for various controlled situations. activities [162], and graded exercise should not be
Through increased awareness of problematic offered [65].
situations, specific strategies are employed and
subsequently generalized to other activities in Pulmonary rehabilitation has been evaluated as a
daily life, supported by the use of metacognitive method for improving outcome after COVID-19 in
skills. The training is centered around tasks that several studies, and it has been shown to improve
involve structured planning, generating alternative physical capacity and health-related quality of life
solutions, practicing feedback, and the ability to in patients with persistent symptoms [163]. Other
appropriately modify chosen plans. studies have shown that exercise-based rehabil-
itation programs also improve dyspnea, anxiety,
Several methods have been evaluated for specific and muscle strength [147]. According to reports
executive impairments. The highest evidence for before the COVID-19 pandemic, aerobic training
training problem-solving skills and the ability to can improve cognitive function [164]. There is
reach set goals is seen with metacognitive strategy some support that pulmonary rehabilitation pro-
training in combination with multimodal feedback grams improve mental and cognitive function after
[153]. COVID-19 [165, 166]. In one of these studies, 64
patients with persistent symptoms after COVID-
Fatigue. Evidence-based treatments for fatigue 19 underwent a 6-week interdisciplinary individ-
are limited [156]. As fatigue is a multidimen- ualized pulmonary rehabilitation program. Apart
sional condition with many contributing factors, from an improvement in the primary effect variable,
the methods also need to be multidimensional 6-min walk distance, there was also an improve-
and preferably team-based. Treatment should be ment in the Fatigue Assessment Scale [166]. In
preceded by an investigation of possible primary another study, a 12-week rehabilitation program
and secondary causes of the patient’s fatigue, was associated with a significant decrease in the
such as general health, depression, sleep distur- proportion of patients reporting having a cognitive
bances, medication side effects, pain, other fatigue- deficit [165]. However, both studies were observa-
inducing illnesses (e.g., anemia and hypothy- tional studies without a control group.
roidism), and physical condition. The patient’s bal-
ance between rest and activity level should also
be mapped. Once underlying causes are identified, Pharmacological treatment
pragmatic and individualized treatments can be Implementation of systemic corticosteroids as
implemented. As with cognitive rehabilitation, the standard of care in the management of severe
interventions can be psychoeducational, compen- COVID-19 during the early phase of the pandemic
satory, or focused on functional training. was based on evidence from clinical trials. In
patients hospitalized with COVID-19, the use
of dexamethasone resulted in reduced 28-day
Physical exercise
mortality among those who were receiving either
Physical exercise and fitness could be helpful for invasive mechanical ventilation or oxygen [167].
fatigue in neurological diseases [157, 158]. The In a systematic review, corticosteroid therapy was

574 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

associated with clinical recovery and a signifi- regarding severity of initial infection, when PCC
cantly shortened length of ICU hospitalization investigation is initiated, certain clusters of PCC
compared to those not treated with corticosteroids symptoms, immune status, comorbidities, demo-
[168]. There are also a few observational studies graphics, and—if possible—virus variant. In addi-
indicating that treatment with systemic steroids tion, there is still a lack of clear clinical markers
confers faster improvement in lung function and indicating which patients are suitable for which
resolution of radiological findings [169, 170]. interventions, a prerequisite for successful rehabil-
Regarding cognitive function, Manera et al. itation in clinical contexts. Pharmacological treat-
assessed cognitive function with Mini-Mental ment regarding cognitive dysfunction also needs
State Examination (MMSE) and found that treat- to be evaluated, as well as whether treatment of
ment with systemic steroids was associated with SARS-CoV-2 or reactivated viruses can produce
improved MMSE scores in a subgroup of patients secondary beneficial effects on cognition.
that had both COVID-19 and concurrent other
infections [171]. Conclusions

Antiviral therapy has become increasingly impor- Prolonged cognitive dysfunction is a common
tant in the management of COVID-19 as an early impairment affecting individuals with PCC. Risk
treatment of mild and moderate disease to pre- factors for PCC in general include female sex, age,
vent high-risk populations from progression to preexisting medical conditions, and the severity of
severe illness [172, 173]. Remdesivir and nir- the acute illness. Proposed mechanisms contribut-
matrelvir/ritonavir are the most frequently used ing to PCC and the cognitive impairments include
antiviral drugs, and in a recent preprint study, neuroinflammation, hypoxia, vascular damage,
patients with acute COVID-19 who received nirma- latent viral reactivation, and direct viral invasion
trelvir were 26% less likely to develop PCC regard- of the central nervous system. Managing cognitive
less of their vaccination status and prior history of dysfunction in PCC requires a multidimensional
SARS-CoV-2 infection [174]. approach including a neuropsychological exami-
nation and individualized rehabilitation. Although
Antithrombotic treatment is recommended for evidence specific to COVID-19-related cognitive
patients with acute severe COVID-19 infection due impairments is limited, interventions based on
to increased risk of venous and arterial thrombo- established practices for other neurological condi-
sis [175, 176]. However, the role of antithrombotic tions can be implemented. The WHO recommends
treatment in PCC remains unclear. education, skills training, cognitive exercises,
assistive products, and environmental modifi-
cations. Functional training carefully monitored
Identified knowledge gaps for intensity is recommended for people who do
not suffer from PEM. Further research is essen-
Specific risk factors associated with the develop-
tial for evidence-based interventions specific to
ment of cognitive dysfunction in PCC need to be
COVID-19-related cognitive impairments.
further explored, such as why women seem to be
overrepresented in this group. There is no specific
Author contributions
cure for PCC generally nor for cognitive dysfunc-
tion specifically. Rather, treatment is focused on Conceptualization (equal); methodology (equal);
symptom management and individualized rehabil- project administration (supporting); visualization
itation. Larger interventional studies regarding the (equal); writing—original draft (equal); writing—
effect on cognitive functions in PCC are still lack- review and editing (equal): Marika Möller. Con-
ing. There are some ongoing studies—for exam- ceptualization (equal); methodology (supporting);
ple, hyperbaric oxygen treatment in PCC (Clinical- writing—original draft (equal); writing—review
Trials.gov Identifier: NCT04842448) and the effect and editing (supporting): Kristian Borg. Con-
of nirmatrelvir/ritonavir on individuals with severe ceptualization (equal); methodology (supporting);
PCC (ClinicalTrials.gov Identifier: NCT05823896)— writing—original draft (equal); writing—review and
but these are small. Preferably, multicenter studies editing (supporting): Christer Janson. Conceptu-
are needed. Potential underlying subgroups that alization (equal); methodology (supporting); project
may respond differently to treatment and/or spe- administration (supporting); writing—original
cific rehabilitation must be identified by careful draft (supporting): Maria Lerm. Conceptualiza-
consideration of the study population recruitment tion (equal); methodology (supporting); visualization

© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 575
Journal of Internal Medicine, 2023, 294; 563–581
 13652796, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13720 by Universita Di Pavia, Wiley Online Library on [08/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Management of cognitive symptoms in PCC / M. Möller et al.

(supporting); writing—original draft (supporting); cohort studies including 1 284 437 patients. Lancet Psychi-
writing—review and editing (equal): Johan Nor- atry. 2022;9(10):815–27.
mark. Conceptualization (equal); methodology 12 Yang X, Hou C, Shen Y, Zhang M, Zhang K, Wang F, et al.
Two-year health outcomes in hospitalized COVID-19 sur-
(equal); project administration (lead); visualization
vivors in China. JAMA Netw Open. 2022;5(9):e2231790.
(equal); writing—original draft (equal); writing— 13 Huang L, Li X, Gu X, Zhang H, Ren L, Guo L, et al. Health
review and editing (lead): Katarina Niward. outcomes in people 2 years after surviving hospitalisation
with COVID-19: a longitudinal cohort study. Lancet Respir
Conflict of interest statement Med. 2022;10(9):863–76.
14 Ahmad I, Edin A, Granvik C, Kumm Persson L, Tevell S,
The authors declare no conflicts of interest. Månsson E, et al. High prevalence of persistent symptoms
and reduced health-related quality of life 6 months after
COVID-19. Front Public Health. 2023;11:1104267.
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